Dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same

ABSTRACT

An object of the present invention is to provide a compound that can be used as a more superior therapeutic agent for central nervous system diseases. The present invention provides a dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-1H-quinolin-2-one or of a salt thereof, and a process for producing the same.

This application. is a continuation of application Ser. No. 15/294,644,filed Oct. 14, 2016, which is a continuation of application. Ser. No.14/396,224, filed Oct. 22, 2014, now U.S. Pat. No. 9,499,525, issuedNov. 22, 2016, which is the National Stage of PCT/JP2013/062681, filedApr. 23, 2013, and claims the benefit of U.S. Provisional ApplicationNo. 61/636,920, filed Apr. 23, 2012 and U.S. Provisional Application No.61/791,378, filed Mar. 15, 2013, all of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a dihydrate of a benzothiophenecompound or of a salt thereof, and a process for producing the same.

BACKGROUND ART

A heterocyclic compound having a specific substituent or substituents isknown as an active ingredient that has serotonin uptake inhibitoryactivity (or serotonin re-uptake inhibitory activity) in addition todopamine D₂ receptor partial agonistic activity (D₂ receptor partialagonistic activity), serotonin 5-HT_(2A) receptor antagonistic activity(5-HT_(2A) receptor antagonistic activity), and adrenaline α₁ receptorantagonistic activity (α₁ receptor antagonistic activity) (PatentLiterature (PTL) 1). This active ingredient has a wide therapeuticspectrum for central nervous system diseases (particularlyschizophrenia).

In the pharmaceutical field, the development of pharmaceuticalpreparations that are suitable according to the severity of disease invarious patients in need of treatment, patient predisposition, and otherfactors, has been desired. Although the heterocyclic compound disclosedin the above PTL 1 is known to have a wide therapeutic spectrum forneurological diseases, the development of a more effective therapeuticagent is currently desired.

CITATION LIST Patent Literature

PTL 1: JP2006-316052A

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a compound that can beused as a more superior therapeutic agent for central nervous systemdiseases.

Solution to Problem

The present inventors conducted extensive research to develop a moresuperior therapeutic agent for central nervous system diseases. As aresult, the inventors found that among the heterocyclic compoundsdisclosed in PTL 1, a specific benzothiophene compound that is in theform of a dihydrate of the benzothiophene compound or of a salt thereof(hereinafter also referred to as the “dihydrate of the presentinvention”) can be the desired therapeutic agent. Further, the presentinventors found that when the dihydrate of the present invention is usedas an intramuscular injection for treating central nervous systemdiseases, it functions as a highly effective pharmacologically activesubstance.

The present invention has been accomplished based on this finding. Thepresent invention provides a novel dihydrate of the benzothiophenecompound represented by Formula (I) or of a salt thereof, which is inthe form of a hydrate, and further provides an industrially advantageousprocess for producing the dihydrate.

The present invention provides a novel dihydrate, a process forproduction thereof, and a benzothiophene compound comprising thedihydrate shown in items 1 to 14.

Item 1. A. dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or of a salt thereof.Item 2. The dihydrate according to item 1 which has characteristic peaksat diffraction angles (2θ) of 8.1°, 8.9°, 15.1°, 15.6°, and 24.4° in anX-ray powder diffraction pattern measured by copper radiation ofλ=1.5418Å through a monochromator.Item 3. The dihydrate according to item 1 or 2 which has characteristicpeaks at 3509 cm⁻¹, 2934 cm⁻¹, 2812 cm⁻¹, 1651 cm⁻¹, 1626 cm⁻¹, 1447cm⁻¹, 1223 cm⁻¹, and 339 cm⁻¹ in an infrared absorption spectrum asmeasured by a potassium bromide tablet method.Item 4. The dihydrate according to any one of items 1 to 3 which hascharacteristic peaks at 1497 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1287cm⁻¹, 1223 cm⁻¹, and 781 cm⁻¹ in a Raman spectrum.Item 5. The dihydrate according to any one of items 1 to 4 whichcontains water in an amount of 6.5 to 8.8 wt. %.Item 6. The dihydrate according to any one of items 1 to 5 which haspeaks in a ¹H-NMR spectrum at:

-   -   1.64 ppm (tt, J=7.4 Hz, J=7.4 Hz, 2 H),    -   1.80 ppm (tt, J=7.0 Hz, J=7.0 Hz, 2 H),    -   2.44 ppm (t, J=7.5 Hz, 2 H),    -   2.62 ppm (br, 4 H),    -   3.06 ppm (br, 4 H),    -   3.32 ppm (s, 4 H+H₂O),    -   4.06 ppm (t, J=6.5 Hz, 2 H),    -   6.29 ppm (d, J=9.5 Hz, 1 H),    -   6.80 ppm (d, J=2.5 Hz, 1 H),    -   6.80 ppm (dd, J=2.5 Hz, J=9.0 Hz, 1 H),    -   6.88 ppm (d, J=7.5 Hz, 1 H),    -   7.27 ppm (dd, J=7.8 Hz, J=7.8 Hz, 1 H),    -   7.40 ppm (dd, J=0.5 Hz, J=5.5 Hz, 1 H),    -   7.55 ppm (d, J=9.0 Hz, 1 H),    -   7.61 ppm (d, J=8.0 Hz, 1 H),    -   7.69 ppm (d, J=5.5 Hz, 1 H),    -   7.80 ppm (d, J=9.5 Hz, 1 H), and    -   11.57 ppm (s, 1 H).        Item 7. A process for producing a dihydrate of 7-[4-(4-benzo        [b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or of        a salt thereof,        the process comprising:        (1) mixing at least one organic acid selected from the group        consisting of acetic acid and lactic acid, an ethanol-water        mixed solution, and        7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)        buxitoxy]-1H-quinolin-2-one to prepare an acid solution;        (2) cooling the solution obtained in step (1) to 5° C. or less;        and        (3) mixing the solution cooled in step (2) with an alkali to        adjust the pH of the solution to 7 or more.        Item 8. A dihydrate of        7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)        butoxy]-1H-quinolin-2-one or of a salt thereof obtained by the        process according to item 7.        Item 9. A benzothiophene compound for use in treating and/or        preventing a central nervous system disease, the compound        comprising the dihydrate according to any one of items 1 to 6        and 8 and an anhydride of        7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)        butoxy]-1H-quinolin-2-one or of a salt thereof, and the        dihydrate being contained in an amount of 60 wt. % or more in        the compound.        Item 10. A method for preventing and/or treating a central        nervous system disease comprising the dihydrate according to any        one of items 1 to 6 and 8 as an active ingredient.        Item 11. The method according to item 10 which is for preventing        or treating a central nervous system disease selected from the        group consisting of schizophrenia, treatment-resistant,        refractory and chronic schizophrenia, emotional disturbance,        psychotic disorder, mood disorder, bipolar disorder, mania,        depression, endogenous depression, major depression, melancholic        and treatment-resistant depression, dysthymic disorder,        cyclothymic disorder, anxiety disorder, somatoform disorder,        factitious disorder, dissociative disorder, sexual disorder,        eating disorder, sleep disorder, adjustment disorder,        substance-related disorder, anhedonia, delirium, cognitive        impairment, cognitive impairment associated with Alzheimer's        disease, Parkinson's disease, and other neurodegenerative        diseases, BPSD caused by cognitive impairment, cognitive        impairment in schizophrenia, cognitive impairment, caused by        treatment-resistant, refractory or chronic schizophrenia,        vomiting, motion sickness, obesity, migraine, pain, mental        retardation, autism, Tourette's syndrome, tic disorder,        attention deficit hyperactivity disorder, conduct disorder, and        Down's syndrome.        Item 12. A dopamine D₂ receptor partial agonist and/or a        5-HT_(2A) receptor antagonist and/or a serotonin uptake        inhibitor and/or a serotonin reuptake inhibitor and/or a α₁        receptor antagonist comprising the dihydrate according to any        one of items 1 to 6 and 8 as an active ingredient.        Item 13. A pharmaceutical composition comprising the dihydrate        according to any one of items 1 to 6 and 8 and a        pharmaceutically acceptable carrier.

According to another embodiment of the present invention, a hydrate ofthe benzothiophene compound described below is provided.

Item 14. A hydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one which has characteristic peaks at diffractionangles (2θ) of 7.7°, 9.4°, 11.8°, 18.9°, and 24.0°in an X-ray powderdiffraction pattern measured by copper radiation of λ=1.5418 Å through amonochromator.

The dihydrate of the present invention and the process for producing thedihydrate are described in detail below.

Process for Producing the Dihydrate of the Benzothiophene Compound or ofa Salt Thereof According to the Present Invention

The benzothiophene compound referred to in the dihydrate of thebenzothiophene compound or of a salt thereof according to the presentinvention is 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one represented by Formula (I).

The dihydrate of the benzothiophene compound represented by Formula (I)or of a salt thereof according to the present invention can be producedfrom an anhydride of the benzothiophene compound or of a salt thereof.

The benzothiophene compound (in the form of an anhydride) of Formula(I), from which the dihydrate of the present invention is produced, is aknown compound, and can be obtained by the production method disclosedin Example 1 of JP2006-316052A or according to Reference Examples 1 and2 described below herein.

The dihydrate of the benzothiophene compound of Formula (I) or of a saltthereof according to the present invention can be produced by steps (1)to (3) described above.

In step (1), at least one organic acid selected from the groupconsisting of acetic acid and lactic acid, an ethanol-water mixedsolution, and the benzothiophene compound of Formula (I) (in the form ofan anhydride) is mixed to prepare an acid solution.

Lactic acid that is used as an organic acid may be D-form, L-form, or amixture thereof.

The ethanol-water mixed solution used in step (1) is preferably preparedso as to contain ethanol in an amount of about 95 volume % or less, morepreferably about 70 volume % or less, and even more preferably about 60volume % or less. When the ethanol-water mixed solution contains ethanolin an amount of 95 volume % or less, a dihydrate of the benzothiophenecompound represented by Formula (I) can be obtained. Although the lowerlimit of the amount of ethanol in the solution is not particularlylimited, it is preferably about 20 volume %, and more preferably about30 volume %.

The concentration of the benzothiophene compound of Formula (I) in theethanol-water mixed solution is preferably about 0.1 to 30 wt. % (w/w%), more preferably about 0.5 to 20 wt. %, and even more preferablyabout 1 to 10 wt. %. When the concentration of the benzothiophenecompound of Formula (I) is set to the aforementioned range, thebenzothiophene compound of Formula (I) can be fully dissolved in theethanol-water mixed solution, and a dihydrate with a higher purity canbe obtained by performing the subsequent steps (steps (2) and (3))described below.

The amount of the organic acid in the ethanol-water mixed solution isnot particularly limited insofar as the system can be adjusted to anacidic condition. For example, the organic acid is preferably containedin an amount of about 0.1 to 20 wt. %, more preferably about 0.3 to 10wt. %, and even more preferably about 0.5 to 5 wt. %.

The amount of the organic acid is not particularly limited, insofar asthe system can be adjusted to an acidic condition. For example, theorganic acid is preferably contained in an amount of about 5 to 100parts by weight, more preferably about 20 to 80 parts by weight, basedon 100 parts by weight of the benzothiophene compound of Formula (I).

The temperature at which the solution is prepared in step (1) is notparticularly limited insofar as the following conditions are met: thebenzothiophene compound of Formula (I) is dissolved in a liquidcontaining the aforementioned organic acid and ethanol-water mixedsolution; ethanol, water, or the organic acid does not vaporize; and thebenzothiophene compound does not decompose. Specifically, thetemperature is preferably about 50 to 120° C., and more preferably about70 to 100° C. A reflux temperature (about 80° C.) may be used.

In step (2) , the solution obtained in step (1) is cooled.

The cooling temperature is 5° C. or less, preferably about 0° C. orless, and more preferably −2° C. or less. When the pH of the solution isadjusted with an alkali in a subsequent step, heat is generated.Therefore, when the cooling temperature is higher than 5° C., the yield.of the dihydrate of the present invention tends to be insufficient. Thelower limit of the cooling temperature in step (2) is not particularlylimited. However, in view of the fact that the temperature must beraised in the subsequent step and that water may be frozen, the lowerlimit of the cooling temperature is preferably about. −20° C., and morepreferably about −10° C.

In step (3), the solution cooled in step (2) is mixed with an alkali toadjust the pH to 7 or more. Examples of the alkali include sodiumhydroxide, potassium hydroxide, and the like.

For mixing the solution cooled in step (2) with an alkali, an aqueousalkali solution prepared in advance may be used. The concentration ofthe aqueous alkali solution is, for example, about 0.1 to 25 wt. %, andmore preferably about 0.5 to 10 wt. %.

To avoid a rapid temperature rise of the mixed solution in the system bythe addition of an alkali (aqueous solution) as described above, thealkali (aqueous solution) is preferably pre-cooled. The temperature ofthe alkali (aqueous solution) is preferably about −5 to 15° C., and morepreferably about −2 to 5° C.,

The amount of alkali is not particularly limited insofar as the solutionin the system can be adjusted to a pH of 7 or more. For example, analkali is preferably added in an amount of about 0.3 to 10 parts byweight, and more preferably about 0.5 to 3 parts by weight, per part byweight of the organic acid incorporated in the solution in step (1).

In step (3), the solution is adjusted with an alkali to a pH of 7 ormore, more preferably about 7.5 or more, and still more preferably about8 or more. When the pH is less than 7, the yield of the dihydrate of thepresent invention tends Co be insufficient. Although the upper limit ofthe pH is not particularly limited, it is preferably, for example, a pHof about 12, and more preferably a pH of about 10, to facilitate thewashing of the precipitated dihydrate of the present invention and theformation of a salt of the benzothiophene compound under stronglyalkaline conditions.

By performing steps (1) to (3), the dihydrate of the present inventionis precipitated.

The precipitated dihydrate of the present invention is separated intosolid and liquid phases by a known method and purified by washing withwater.

Preferably, the obtained dihydrate of the benzothiophene compound ofFormula (I) or of a salt thereof is heated to about 10° C. or higher,and more preferably about 10 to about 50° C.

Dihydrate of the Benzothiophene Compound of Formula (I) or of a SaltThereof

The physicochemical properties of the dihydrate of the present inventionobtained by the above production process are shown below.

The crystalline form of the dihydrate of the present invention obtainedby the above production process may include a hydrate of thebenzothiophene compound or of a salt thereof obtained by the aboveproduction process according to another embodiment of the presentinvention.

X-Ray Powder Diffraction

The dihydrate of the present invention. is identified by an X-ray powderdiffraction pattern measured by copper radiation of λ=1.5418 Å through amonochromator. The dihydrate of the present invention has peaks shown inFIG. 2 in the X-ray powder diffraction pattern, and has characteristicpeaks at the following diffraction angles (2θ) in the X-ray powderdiffraction pattern. These peaks are different from the peaks of theknown benzothiophene compound of Formula (I) (in the form of ananhydride).

Diffraction angles (2θ)

-   -   8.1°    -   8.9°    -   15.1°    -   15.6°    -   24.4°

The dihydrate of the present invention has peaks at the followingdiffraction angles (2θ) as shown in FIG. 2, in addition to theaforementioned peaks.

Diffraction angles (2θ)

11.6°, 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°, 20.5°, 21.5°,22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°, 28.1°, 28.5°, 28.9°, 29.8°,30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°, 36.7°, 37.4°,38.3°.

Although the above diffraction angles (2θ) may contain an error of −0.2to +0.2° according to the measuring apparatus, measurement conditions,etc., such a level of error is within an acceptable range in the presentinvention.

Infrared Absorption Measurement

The dihydrate of the present invention is identified by an infraredabsorption spectrum measured by the potassium, bromide tablet method. Inthe infrared absorption spectrum, the dihydrate of the present inventionhas a spectrum shown in FIG. 3, and has peaks at the followingwavenumbers (cm⁻¹):

Wavenumbers

-   -   3509 cm⁻¹    -   2934 cm⁻¹    -   2812 cm⁻¹    -   1651 cm⁻¹    -   1626 cm⁻¹    -   1447 cm⁻¹    -   1223 cm⁻¹    -   839 cm⁻¹

The dihydrate of the present invention has peaks at the wavenumbersshown in FIG. 3, in addition to the aforementioned peaks.

Although the wavenumbers (cm⁻¹) may contain an error of −0.5 to +0.5%according to the measuring apparatus, measurement conditions, etc., sucha level of error is within an acceptable range in the present invention.

The dihydrate of the present invention is identified by a Ramanspectrum. The dihydrate of the present invention has the spectrum shownin FIG. 4 and has peaks in the vicinity of the following wavenumbers(cm⁻¹):

Wavenumbers

-   -   1497 cm⁻¹    -   1376 cm⁻¹    -   1323 cm⁻¹    -   1311 cm⁻¹    -   1287 cm⁻¹    -   1223 cm⁻¹    -   781 cm⁻¹

The dihydrate of the present invention has peaks in the vicinity of thefollowing wavenumbers as shown in FIG. 4, in addition to theaforementioned peaks:

Wavenumbers

1656 cm⁻¹, 1613 cm−1, 1563 cm⁻¹, 1512 cm⁻¹, 1468 cm⁻¹, 1446 cm⁻¹, 1241cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1096 cm⁻¹, 1070 cm⁻¹, 971 cm⁻¹, 822 cm¹

Water Content

The dihydrate of the present invention contains water in an amount of6.5 to 8.8 wt. %, and more specifically 7.3 to 8.1 wt. %. The watercontent is measured by the Karl Fischer method.

¹H-NMR Measurement

The dihydrate of the present invention is identified by peaks measuredby ¹H-NMR spectroscopy. The dihydrate of the present invention has the¹H-NMR spectrum shown in FIG. 1, and has proton peaks in the ¹H-NMRspectrum measured in Example 1 below.

The hydrate of the benzothiophene compound of Formula (I) according toanother embodiment of the present invention is obtained during theprocess of producing the dihydrate as described above. Thephysicochemical properties of the hydrate are shown below.

X-Ray Powder Diffraction

The hydrate of the benzothiophene compound of Formula (I) according toanother embodiment of the present invention has peaks shown in FIG. 10in an X-ray powder diffraction pattern measured in the same manner asabove, and has characteristic peaks at the following diffraction angles(2θ). These peaks are different from the peaks of the knownbenzothiophene compound of Formula (I) (in the form of an anhydride) inthe X-ray powder diffraction pattern.

Diffraction angles (2θ)

-   -   7.7°    -   9.4°    -   11.8°    -   18.9°    -   24.0°

The hydrate of the benzothiophene compound of Formula (I) according toanother embodiment of the present invention has peaks at the followingdiffraction angles (2θ) as shown in FIG. 10, in addition to theaforementioned peaks.

Diffraction angles (2θ)

5.7°, 8.1°, 8.8°, 10.7°, 12.6°, 13.6°, 13.9°, 15.0°, 15.6°, 16.6°,17.2°, 17.7°, 13.8°, 20.4°, 21.2°, 21.6°, 22.2°, 23.1°, 25.2°, 25.8°,26.7°, 27.2°, 27.9°, 28.7°, 29.3°, 30.2°, 31.2°, 33.4°

Benzothiophene Compound Containing the Dihydrate of the PresentInvention

The present invention further provides a benzothiophene compoundcomprising a dihydrate of the benzothiophene compound of Formula (I) orof a salt thereof and an anhydride of the benzothiophene compound ofFormula (I) or of a salt thereof. The benzothiophene compound can beused as a therapeutic and/or prophylactic agent for central nervoussystem diseases.

The dihydrate of the benzothiophene compound of Formula (I) or of a saltthereof may consist only of the dihydrate of the present invention ormay be in the form of a mixture of the dehydrate of the presentinvention with a hydrate of the benzothiophene compound of Formula (I)according to another embodiment of the present invention.

The benzothiophene compound preferably contains the dihydrate in anamount of 60 wt. % or more, preferably 80 wt. % or more, and morepreferably 90 wt. % or more.

The dihydrate of the present invention may be further pulverized to adesired mean particle diameter. Pulverization methods that can be usedinclude dry-milling processes and wet-milling processes. Examples ofmills usable in such milling processes include jet mills, ball mills(e.g., Dyno-Mill), and other low-energy mills (e.g., roller mills), andhigh-energy mills. Examples of high-energy mills include Netzsch mills,DC mills, planetary mills, and the like. The pulverized dihydrate of thepresent invention preferably has a mean particle diameter of about 1 to10 μm, more preferably about 2 to 8 μm, and even more preferably about 2to 6 μm. The pulverized dihydrate is included within the scope of thedihydrate of the present invention.

The term “mean particle diameter” as used herein refers to the volumemean diameter as measured by a laser-light-scattering (LLS) method.Particle size distribution is measured by an LLS method, and meanparticle diameter is calculated from the particle size distribution.

The salt referred to in the dihydrate of the benzothiophene compound ofFormula (I) or of a salt thereof is not particularly limited insofar asit is a pharmaceutically acceptable salt. Examples of salts includealkali metal salts (e.g., sodium salts and potassium salts), alkalineearth metal salts (e.g., calcium salts and magnesium salts), and likemetal salts; ammonium salts, alkali metal carbonates (e.g., lithiumcarbonate, potassium carbonate, sodium carbonate, and cesium carbonate),alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate,sodium hydrogen carbonate, and potassium hydrogen carbonate), alkalimetal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, and cesium hydroxide), and like salts of inorganic bases;tri(lower)alkylamines (e.g., trimethylamine, trimethylamine, andN-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole,picoline, dimethylaminopyridine, dimethylaniline,N-(lower)alkyl-morpholines (e.g., N-methylmorpholine),1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and like salts of organicbases; and hydrochloride, hydrobromate, hydroiodide, sulfate, nitrate,phosphate, and like salts of inorganic acids; formate, acetate,propionate, oxalate, malonate, succinate, fumarate, maleate, lactate,malate, citrate, tartrate, carbonate, picrate, methanesulfonate,ethanesulfonate, p-toluenesulfonate, glutamate, and like salts oforganic acids. The term, “(lower) alkyl” as used herein refers to an“alkyl having 1 to 6 carbon atoms.”

The dihydrate of the benzothiophene compound of Formula (I) or of a saltthereof may be pharmaceutically acceptable co-crystals or co-crystalsalts. The term “co-crystal or co-crystal salt” as used herein means acrystalline material comprised of two or more unique solids at roomtemperature, each containing distinctive physical characteristics (suchas structure, melting point, and heat of fusion). Co-crystals andco-crystal salts can be produced according to known co-crystallizationmethods.

Pharmaceutical Preparation Containing the Dihydrate of the PresentInvention

The dihydrate of the present invention is usable as a pharmaceuticalpreparation for treating central nervous system diseases.

The pharmaceutical preparation is used in the form of an ordinarypharmaceutical preparation, and is prepared using various generally useddiluents and excipients, such as fillers, extenders, binders,moisturizing agents, disintegrators, surfactants, lubricants, etc. Theform of such a pharmaceutical preparation can be selected according tothe purpose of the therapy. Typical examples include tablets, pills,powders, solutions, suspensions, emulsions, granules, capsules,suppositories, injections (solutions, suspensions, etc.) and the like.

To form tablets, any of various carriers conventionally known in thisfield can be used. Examples thereof include lactose, white sugar, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid, and other excipients; water, ethanol, propanol,simple syrup, glucose solutions, starch solutions, gelatin solutions,carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,polyvinylpyrrolidone and other binders; dry starch, sodium alginate,agar powder, laminarin powder, sodium hydrogen carbonate, calciumcarbonate, fatty acid esters of polyoxyethylene sorbitan, sodium laurylsulfate, stearic acid monoglycerides, starch, lactose, and otherdisintegrators; white sugar, stearin, cacao butter, hydrogenated oils,and other disintegration inhibitors; quaternary ammonium bases, sodiumlauryl sulfate, and other absorption promoters; glycerol, starch, andother moisturizing agents; starch, lactose, kaolin, bentonite, colloidalsilicic acid, and other adsorbents; purified talc, stearates, boric acidpowder, polyethylene glycol, and other lubricants; etc. Further, suchtablets may be coated with typical coating materials as required, toprepare, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double- or multi-layeredtablets, etc.

To form pills, any of various carriers conventionally known in thisfield can be used. Examples thereof include glucose, lactose, starch,cacao butter, hydrogenated vegetable oils, kaolin, talc, and otherexcipients; powdered acacia, powdered tragacanth, gelatin, ethanol, andother binders; laminarin, agar, and other disintegrators; etc.

To form suppositories, any of various carriers conventionally known inthis field can be used. Examples thereof include polyethylene glycol,cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

Capsules can be prepared by mixing the active ingredient with anabove-mentioned carrier and enclosing the result in a hard gelatincapsule, soft capsule, or the like.

To form injectable preparations, a solution, emulsion or suspension issterilized and preferably made isotonic to blood. Any of the diluentewidely used for such forms in this field can be employed to form theinjectable preparation. Examples of such diluents include water,ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol,polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylenesorbitan, etc.

In this case, the pharmaceutical preparation may contain sodiumchloride, glucose or glycerol in an amount sufficient to prepare anisotonic solution, and may contain conventional solubilizers, buffers,analgesic agents, etc. Further, if necessary, the pharmaceuticalpreparation may contain coloring agents, preservatives, fragrances,flavors, sweetening agents, etc., and/or other medicines.

The amount of the dihydrate of the present invention contained in thepharmaceutical preparation is not limited, and can be suitably selectedfrom a wide range. The amount is generally about 1 to 70% by weight, andpreferably about 1 to 30% by weight of the pharmaceutical preparation.

The route of administration of the pharmaceutical preparation of thepresent invention is not particularly limited, and the preparation isadministered by a route suitable to the form of the preparation, thepatient's age, sex and other conditions, and the status of the disease.For example, tablets, pills, solutions, suspensions, emulsions, granulesand capsules are administered orally. Injectable preparations areintravenously administered singly or mixed with typical injectiontransfusions, such as glucose solutions, amino acid solutions or thelike, or singly administered intramuscularly, intracutaneously,subcutaneously or intraperitoneally, as required. Suppositories areadministered intrarectally.

The dosage of the pharmaceutical preparation of the present invention issuitably selected according to the method of use, the patient's age, sexand other conditions, and the severity of the disease. The amount ofactive ingredient is usually about 0.1 to 10 mg/kg body weight/day.Further, it is desirable that the pharmaceutical preparation in eachunit of the administration form contain the active ingredient in anamount of about 1 to 200 mg.

Specific examples of the central nervous system diseases treated by thepharmaceutical preparation containing the dihydrate of the presentinvention include schizophrenia, such as treatment-resistant, refractoryand chronic schizophrenia, emotional disturbance, psychotic disorder,mood disorder, bipolar disorder (e.g., bipolar I disorder and bipolar IIdisorder), mania, depression, endogenous depression, major depression,melancholic and treatment-resistant depression, dysthymic disorder,cyclothymic disorder, anxiety disorder (e.g., panic attack, panicdisorder, agoraphobia, social phobia, obsessive-compulsive disorder,post traumatic stress disorder, generalized anxiety disorder, and acutestress disorder), somatoform disorder (e.g., hysteria, somatizationdisorder, conversion disorder, pain disorder, and hypochondria),factitious disorder, dissociative disorder, sexual disorder (e.g.,sexual dysfunction, libido disorder, sexual arousal disorder, anderectile dysfunction), eating disorder (e.g., anorexia nervosa andbulimia nervosa), sleep disorder, adjustment disorder, substance-relateddisorder (e.g., alcohol abuse, alcohol intoxication and drug addiction,amphetamine addiction, and narcotism), anhedonia (e.g., iatrogenicanhedonia, anhedonia of a psychic or mental cause, anhedonia associatedwith depression, anhedonia associated with schizophrenia), delirium,cognitive impairment, cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease, and other neurodegenerative diseases, BPSD(Behavioral and Psychological Symptoms of Dementia) caused by cognitiveimpairment, cognitive impairment in schizophrenia, cognitive impairmentcaused by treatment-resistant, refractory or chronic schizophrenia,vomiting, motion sickness, obesity, migraine, pain, mental retardation,autistic disorder (autism), Tourette's syndrome, tic disorder, attentiondeficit hyperactivity disorder, conduct disorder, Down's syndrome, etc.;and various other central nervous system diseases. The pharmaceuticalpreparation containing the dihydrate of the benzothiophene compound isextremely effective for the amelioration of these central nervous systemdiseases.

ADVANTAGEOUS EFFECTS OF INVENTION

The present invention provides a novel dihydrate of the benzothiophenecompound represented by Formula (I) or of a salt thereof. The presentinvention also enables the production of a desired dihydrate in anindustrially advantageous manner by employing a specific manufacturingmethod for the benzothiophene compound represented by Formula (I) or asalt thereof.

Furthermore, the present invention is advantageous in that when thedihydrate is used as a drug, its pharmacological effect can beremarkably retained after administration to a patient.

When the dihydrate of the present invention is used as the activeingredient of an intramuscular injectable preparation, stimulation afterintramuscular injection is low and thus effective.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1. shows the ¹H-NMR spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) prepared in Example 1.

FIG. 2 shows the X-ray powder diffraction pattern of the dihydrate ofthe benzothiophene compound represented by Formula (I) prepared inExample 1.

FIG. 3 shows the infrared absorption spectrum of the dihydrate of thebenzothiophene compound represented by Formula (I) prepared in Example1.

FIG. 4 shows the Raman spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) prepared in Example 1.

FIG. 5 shows the ¹H-NMR spectrum of the benzothiophene compoundrepresented by Formula (I) prepared in Example 2.

FIG. 6 shows the X-ray powder diffraction pattern of the dihydrate ofthe benzothiophene compound represented by Formula (I) prepared inExample 2.

FIG. 7 shows the infrared absorption spectrum of the dihydrate of thebenzothiophene compound represented by Formula (I) prepared in Example2.

FIG. 8 shows the Raman spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) prepared in Example 2.

FIG. 9 shows the Ramar spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) prepared in Example 3.

FIG. 10 shows the X-ray powder diffraction pattern of the dihydrate ofthe benzothiophene compound represented by Formula (I) prepared inReference Example 3.

FIG. 11 shows the ¹H-NMR spectrum of the anhydride of the benzothiophenecompound represented by Formula (I) prepared in Comparative Example 1.

FIG. 12 shows the X-ray powder diffraction pattern of the anhydride ofthe benzothiophene compound prepared in Comparative Example 1.

FIG. 13 shows the infrared absorption spectrum of the anhydride of thebenzothiophene compound prepared in Comparative Example 1.

FIG. 14 is a graph showing the mean blood concentration-time profile ofCompound (I) after being injected into the thigh muscle of a dog.

DESCRIPTION OF EMBODIMENTS EXAMPLES

The present invention is described in further detail with reference toExamples and Test Examples. However, the scope of the invention is notlimited to these Examples.

Reference Example 1: Synthesis of 7-(4-chlorobutoxy)-1H-quinolin-2-one

Methanol (149 L), 7-hydroxy-1H-quinolin-2-one (14.87 kg), and potassiumhydroxide (6.21 kg) were mixed and stirred. After dissolution,1-bromo-4-chlorobutane (47.46 kg) was further added thereto and theresulting mixture was stirred under reflux for seven hours. Thereafter,the mixture was stirred at 10° C. for one hour. The precipitated crystalwas centrifuged and washed with methanol (15 L). The wet crystal wascollected and placed in a tank. Water (149 L) was added thereto,followed by stirring at room temperature. After centrifugation, theresulting solid was washed with water (30 L). The wet crystal wascollected and placed in a tank. After adding methanol (74 L), themixture was stirred under reflux for one hour, cooled to 10° C., andthen stirred. The precipitated crystal was centrifuged and washed withmethanol (15 L). The separated crystal was dried at 60° C. to obtain7-(4-chlorobutoxy)-1H-quinolin-2-one (15.07 kg).

Reference Example 2: Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

Water (20 L), potassium carbonate (1.84 kg),1-benzo[b]thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol(8 L) were mixed and stirred at 50° C. 7-(4-Chlorobutoxy)-1H-quinolin-2-one (2.80 kg) obtained in Reference Example 1 was addedto the mixture and stirred under reflux for nine hours. Afterconcentrating the solvent (8 L) under ordinary pressure, the mixture wasstirred at 90° C. for one hour and then cooled to 9° C. The precipitatedcrystal was centrifuged and then sequentially washed with water (8 L)and ethanol (6 L). The separated crystal was dried at 60° C. to obtain acrude product. The crude product (4.82 kg) and ethanol (96 L) were mixedin a reaction vessel, and acetic acid (4.8 L) was introduced into thereaction vessel. The mixture was stirred under reflux for one hour todissolve the crude product. After introducing hydrochloric acid (1.29kg), the mixture was cooled to 10° C. The mixture was heated again,refluxed for one hour, and cooled to 7° C. The precipitated crystal wascentrifuged and washed with ethanol (4.8 L). The separated crystal wasdried at 60° C. to obtain7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin -2-onehydrochloride (5.09 kg). The resulting 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride(5.00 kg), ethanol (45 L), and water (30 L) were mixed in a reactionvessel. The mixture was stirred under reflux to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin1-yl) butoxy]-1H-quinolin-2-onehydrochloride. Activated carbon (500 g) and water (5 L) were addedthereto, and an activated carbon treatment was conducted under refluxfor 30 minutes. After performing hot filtration, a solution containingsodium hydroxide (511 g) dissolved in water (1.5 L) was flowed into thereaction vessel while stirring the filtrate under reflux. After stirringunder reflux for 30 minutes, water (10 L) was introduced thereto and themixture was cooled to approximately 40° C. The precipitated crystal wascentrifuged and washed with water (125 L). The separated crystal wasdried at 80° C. to obtain 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (3.76 kg).

Example 1: Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneDihydrate

The7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-)butoxy]-1H-quinolin-2-one(3.2 kg) obtained in Reference Example 2, ethanol (64 L), water (74 L),and acetic acid (1.77 kg) were mixed in a reaction vessel to prepare anacidic liquid mixture. The mixture was stirred under reflux to dissolvethe7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(reflux temperature: 84° C.). After cooling to −5° C., the solutionobtained above was introduced, over a period of 30 minutes, into asolution containing 25% sodium hydroxide (5.9 kg) and water (54 L) thatwas cooled to 0° C., to prepare a liquid mixture with pH10. After beingstirred at 5° C. or below for one hour, the mixture was heated to 20 to30° C. and further stirred for seven hours. The precipitated crystal wasfiltered and washing with water (320 L) was performed until alkali inthe solid component disappeared (i.e., until the pH value of thefiltrate became 7). The solid component was then air-dried until itsweight became constant to obtain a white solid 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one dihydrate(unground, 3.21 kg).

FIG. 1 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of the dihydrateprepared by the aforesaid method. As shown in FIG. 1, in the ¹H-NMRspectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J=7.4 Hz,J=7.4 Hz, 2 H), 1.80 ppm (tt, J=7.0 Hz, J =7.0 Hz, 2 H), 2.44 ppm (t,J=7.5 Hz, 2 H), 2.62 ppm (br, 4 H), 3.06 ppm (br, 4 H), 3.32 ppm (s, 4H+H₂O), 4.06 ppm (t, J=6.5 Hz, 2 H), 6.29 ppm (d, J=9.5 Hz, 1 H), 6.80ppm (d, J=2.5 Hz, 1 H), 6.80 ppm (dd, J=2.5 Hz, J=9.0 Hz, 1 H), 6.88 ppm(d, J=7.5 Hz, 1 H), 7.27 ppm (dd, J=7.8 Hz, J=7.8 Hz, 1 H), 7.40 ppm(dd, J=0.5 Hz, J=5.5 Hz, 1 H), 7.55 ppm (d, J=9.0 Hz, 1 H), 7.61 ppm (d,J=8.0 Hz, 1 H), 7.69 ppm (d, J=5.5 Hz, 1 H), 7.80 ppm (d, J=9.5 Hz, 1H), and 11.57 ppm (s, 1 H).

The X-ray powder diffraction spectrum of the dihydrate prepared by theaforesaid method was measured using an X-ray diffractometer (D8 ADVANCE,available from Bruker AXS). FIG. 2 shows the X-ray powder diffractionspectrum. As shown in FIG. 2, in the X-ray powder diffraction spectrum,diffraction peaks were observed at 2θ=8.1°, 8.9°, 15.1°, 15.6°, and24.4°. Other than those mentioned above, the diffraction peaks were alsoobserved at 2θ=11.6°, 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°,20.5°, 21.5°, 22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°, 28.1°, 28.5°,28.9°, 29.8°, 30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°,36.7°, 37.4°, and 38.3°.

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid methodwas measured. FIG. 3 shows the IR (KBr) spectrum. As shown in FIG. 3, inthe IR (KBr) spectrum, absorption bands were observed in the vicinity ofwavenumbers 3509 cm⁻¹, 2934 cm⁻¹, 2812 cm⁻¹, 1651 cm⁻¹, 1626 cm⁻¹, 1447cm⁻¹, 1223 cm⁻¹ and 839 cm⁻¹.

The Raman spectrum of the dihydrate prepared by the aforesaid method wasmeasured. FIG. 4 shows the Raman spectrum. As shown in FIG. 4, in theRaman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1497 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1287 cm⁻¹, 1223cm⁻¹, and 781 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1613 cm⁻¹, 1563 cm⁻¹, 1468 cm⁻¹, 1446cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1144 cm⁻¹, 1096 cm⁻¹, 1070 cm⁻¹, 971 cm⁻¹,and 822 cm⁻¹.

The water content of the dihydrate prepared by the aforesaid method wasmeasured using a moisture meter (CA-100, available from MitsubishiChemical Analytech Co., Ltd.) by the Karl Fischer method. As a result,the dihydrate had a water content of 7.79% by weight.

Example 2: Preparation of Finely Ground Dihydrate

Dihydrate crystal (2.73 kg) obtained in Example 1 was ground using a jetmill. Here, the air pressure was set at 5 kgf/cm², and the rotationalspeed of the feeder was set at 20 rpm. As a result, finely ground7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onedihydrate (2.61 kg, 95.6%) was obtained.

The dihydrate (finely ground product) thus obtained had a mean particlediameter of 5.5 μm. The mean particle diameter was measured using aMicrotrack HRA, manufactured by Nikkiso Co., Ltd.

FIG. 5 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of the dihydrateprepared by the above method. As shown in FIG. 5, in the ¹H-NMR spectrum(DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J=7.3 Hz, J=7.3 Hz,2 H), 1.80 ppm (tt, J=6.9 Hz, J=6.9 Hz, 2 H), 2.44 ppm (t, J=7.3 Hz, 2H), 2.62 ppm (br, 4 H), 3.06 ppm (br, 4 H), 3.32 ppm (s, 4 H+H₂O), 4.06ppm (t, J=6.5 Hz, 2 H), 6.29 ppm (d, J=9.5 Hz, 1 H), 6.80 ppm (d, J=2.5Hz, 1 H), 6.80 ppm (dd, J=2.3 Hz, J=9.3 Hz, 1 H), 6.88 ppm (d, J=7.5 Hz,1 H), 7.27 ppm (dd, J=8.0 Hz, J=8.0 Hz, 1 H), 7.40 ppm (d, J=5.5 Hz, 1H), 7.55 ppm (d, J=9.5 Hz, 1 H), 7.61 ppm (d, J=8.0 Hz, 1 H), 7.69 ppm(d, J=5.5 Hz, 1 H), 7.80 ppm (d, J=9.5 Hz, 1 H), and 11.57 ppm (s, 1 H).

The X-ray powder diffraction spectrum of the dihydrate prepared by theaforesaid method was measured in the same manner as in Example 1. FIG. 6shows the X-ray powder diffraction spectrum. As shown in FIG. 6, in theX-ray powder diffraction spectrum, diffraction peaks were observed at2θ=8.2°, 8.9°, 15.2°, 15.7° and 24.4°.

Other than those mentioned above, the diffraction peaks were alsoobserved at 2θ=6.8°, 12.2°, 14.0°, 14.5°, 17.4°, 18.1°, 18.5°, 19.0°,19.2°, 19.6°, 20.3°, 20.6°, 21.5°, 22.7°, 23.4°, 25.0°, 26.1°, 27.1°,28.6°, 29.0°, 30.4°, 34.0°, 34.5°, 35.3°, and 36.7°.

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid methodwas measured in the same manner as in Example 1. FIG. 7 shows the IR(KBr) spectrum. As shown in FIG. 7, in the IR (KBr) spectrum, absorptionbands were observed in the vicinity of wavenumbers 3507 cm⁻¹, 2936 cm⁻¹,2812 cm⁻¹, 1651 cm⁻¹, 1626 cm⁻¹, 1447 cm⁻¹, 1223 cm³¹¹ and 839 cm⁻¹.

The Raman spectrum of the dihydrate prepared by the aforesaid method wasmeasured. FIG. 8 shows the Raman spectrum. As shown in FIG. 8, in theRaman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1496 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1286 cm⁻¹, 1223cm⁻¹, and 781 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1614 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹, 1467cm⁻¹, 1446 cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1095 cm⁻¹, 1069 cm⁻¹,971 cm⁻¹, and 822 cm⁻¹.

The water content of the dihydrate prepared by the aforesaid method wasmeasured using a moisture meter (CA-100, available from MitsubishiChemical Analytech Co., Ltd.) by the Karl Fischer method. As a result,the dihydrate had a water content of 6.74% by weight.

Example 3: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one dihydrate

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid (2.29 kg)were mixed to prepare an acidic liquid mixture. The liquid mixture wasstirred under reflux to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin -2-one(reflux temperature: 82° C.). After cooling to −5° C., the solutionobtained above was introduced, over a period of about 15 minutes, into asolution containing sodium hydroxide (1.48 kg) and water (−135 L) thatwas cooled to 1° C., to prepare a liquid mixture with pH11. After beingstirred at approximately 2 to 5° C. for three hours, the mixture washeated to 45° C. and further stirred at 45 to 50° C. for two hours. Theprecipitated crystal was filtered and washing with water (200 L) wasperformed until alkali in the solid component disappeared (i.e., untilthe pH value of the filtrate became 7). The solid component was furtherwashed with a liquid mixture of ethanol (15 L) and water (20 L). Thesolid component was then dried at room temperature until its weightbecame constant to obtain a white solid 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one dihydrate(unground, 5.11 kg).

The dihydrate thus obtained was the same as that obtained in Example 1.

The Raman spectrum of the dihydrate prepared by the aforesaid method wasmeasured. FIG. 9 shows the Raman spectrum. As shown in FIG. 9, in theRaman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1497 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1287 cm⁻¹, 1223cm⁻¹and 782 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1614 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹,1468cm⁻¹, 1446 cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1126 cm⁻¹, 1096cm⁻¹, 1070 cm⁻¹, 972 cm⁻¹, and 822 cm⁻¹.

Reference Example 3

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneanhydride (7 g), ethanol (140 mL), water (161 ml), and lactic acid (2.7mL) were mixed in a reaction vessel. The mixture was heated to refluxwhile being stirred to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin -2-oneanhydride. After being cooled to approximately −10° C., the solutionobtained above was introduced, while being stirred, into a solutioncontaining sodium hydroxide (2.1 g) and water (189 mL) that was cooledto approximately 0° C. After being stirred at a temperature ofapproximately 0° C. for 3 hours, solid-liquid separation was performed.

The X-ray powder diffraction spectrum of the hydrate prepared by theaforesaid method was measured in the same manner as in Example 1. FIG.10 shows the X-ray powder diffraction spectrum. In the X-ray powderdiffraction spectrum, diffraction peaks were observed at 2θ=7.7°, 9.4°,11.8°, 18.9°, and 24.0°. Other than those mentioned above, diffractionpeaks were also observed at 2θ=5.7°, 8.1°, 8.8°, 10.7°, 12.6°, 13.6°,13.9°, 15.0°, 15.6°, 16.6°, 17.2°, 17.7°, 19.8°, 20.4°, 21.2°, 21.6°,22.2°, 23.1°, 25.2°, 25.8°, 26.7°, 27.2°, 27.9°, 28.7°, 29.3°, 30.2°,31.2°, and 33.4°.

Comparative Example 1: Preparation of7[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneAnhydride

The 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (700 g) prepared in Reference Example 2,ethanol (14 L), and acetic acid (1.4 L) were mixed in a reaction vessel.The mixture was heated to the reflux temperature (76° C.) to dissolve7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-1H-quinolin-2-one.Concentrated hydrochloric acid (158 mL) was further added thereto andthen cooled to 10° C. while being stirred. Thereafter, the mixture washeated again, stirred under reflux for one hour, and then cooled to 8°C. The precipitated solid was filtered by suction and washed withethanol (0.7 L). The solid component was then dried at 60° C. until itsweight became constant to obtain a white solid 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride(814 g). 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one hydrochloride (800 g) , ethanol (7.2 L), andwater (4.8 L) were mixed in a reaction vessel, and the mixture washeated to the reflux temperature (80° C.) while being stirred. Afterperforming hot filtration, the mixture was heated again to 78° C., andthe crystal precipitated in the filtrate was dissolved. A solutioncontaining sodium hydroxide (81.6 g) dissolved in water (240 ml) wasflowed into the above-obtained solution and the mixture was stirredunder reflux for 30 minutes. Water (2.4 L) was added to the mixture,followed by cooling to 40° C. while being stirred. The precipitatedsolid was filtered and washed with water (16 L). The solid was dried at80° C. to obtain a white solid7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-1H-quinolin-2-oneanhydride (637 g).

The ¹H-NMR spectrum of the anhydride obtained above was measured in thesame manner as in Example 1. FIG. 11 shows the ¹H-NMR spectrum (DMSO-d₆,TMS). As shown in FIG. 11, in the ¹H-NMR spectrum (DMSO-d₆, THS), peakswere observed at 1.63 ppm (tt, J=7.3 Hz, J=7.1 Hz, 2 H), 1.80 ppm (tt,J=7.3 Hz, J=6.3 Hz, 2 H), 2.44 ppm (t, J=7.1 Hz, 2 H), 2.61 ppm (m, 4H), 3.05 ppm (m, 4 H), 4.05 ppm (t, J=6.3 Hz, 2 H), 6.29 ppm (d, J=9.5Hz, 1 H), 6.80 ppm (d, J=2.5 Hz, 1 H), 6.80 (dd, J=9.4 Hz, J=2.5 Hz, 1H), 6.88 ppm (dd, J=7.8 Hz, 0.8 Hz, 1 H), 7.27 ppm (dd, J=7.8 Hz, J=7.8Hz, 1 H), 7.39 ppm (dd, J=5.6 Hz, 0.8 Hz, 1 H), 7.55 ppm (d, J=9.4 Hz, 1H), 7.61 ppm (d, J=7.8 Hz, 1 H), 7.69 ppm. (d, J=5.6 Hz, 1 H), 7.80 ppm.(d, J=9.5 Hz, 1 H), and 11.60 (s, 1 H).

The X-ray powder diffraction spectrum of the anhydride obtained abovewas measured in the same manner as in Example 1. FIG. 12 shows the X-raypowder diffraction spectrum. As shown in FIG. 12, in the X-ray powderdiffraction. spectrum, diffraction peaks were observed at 2θ=14.4°,19.1°, 20.2°, 21.3, and 23.2°.

The IR (KBr) spectrum of the anhydride obtained above was measured inthe same manner as in Example 2. FIG. 13 shows the IR (KBr) spectrum. Asshown in FIG. 13, the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one had absorptionbands in the IR (KBr) spectrum in the vicinity of wavenumbers 2941 cm⁻¹,2818 cm⁻¹, 1655 cm⁻¹, 1624 cm⁻¹, 1449 cm⁻¹, 1221 cm⁻¹ and 833 cm⁻¹.

The water content of the anhydride prepared by the aforesaid method wasmeasured in the same manner as in Example 2. The result revealed thatthe anhydride that was obtained had a water content of 0.04% by weight.

Test Example 1: Measurement of Drug Residue in Muscle

The dihydrate of the present invention (150 mg) was dispersed to thesuspension medium (1 mL) described below, and pulverized using 5 mmzirconia beads (1.2 g, pulverization time: 30 min) while being stirredwith a stirrer. The suspension medium used for pulverization was asolution containing 0.832% (w/v) sodium carboxymethylcellulose (CMC-Na),4.16% (w/v) mannitol, and 0.074% (w/v) sodium dihydrogenphosphatemonohydrate. The pH thereof was adjusted to 7.0 by adding an appropriateamount of sodium hydroxide. The concentration of each preparation wasadjusted to 100 mg/mL using this medium.

The dihydrate (finely ground product) thus obtained had a mean particlediameter of 3.5 μm. An anhydride was subjected to pulverization in thesame manner to obtain an anhydride (finely ground product) having a meanparticle diameter of 3.5 μm. The mean particle diameter was measuredusing a laser diffraction particle size analyzer (SALD-3000J orSALD-3100, manufactured by Shimadzu Corporation).

Injectable preparations each containing the dihydrate of the presentinvention (finely ground product, mean particle diameter: 3.5 μm) or ananhydride (finely ground product, mean particle diameter: 3.5 μm) wereobtained by the procedure described above. Table 1 shows theformulations thereof.

Each injectable preparation thus obtained was intramuscularly injectedinto a rat in a dosage of 25 mg/kg. Each injectable preparation wasinjected into three rats. 56 days after the injection, the rats weredissected, and the number of rats exhibiting drug residue in muscle wascounted. Table 2 shows the results.

TABLE 1 Formulations Active ingredient 100 mg Sodium 8.32 mgcarboxymethylcellulose Mannitol 41.6 mg Sodium 0.74 mgdihydrogenphosphate monohydrate Sodium hydroxide Q.S. (adjusted to pH 7)Distilled water Q.S. Total 1 mL

TABLE 2 The number having residue in muscle (Number having Activeingredient residue/Total) Dihydrate 3/3 Anhydride 0/3

Test Example 2: Pharmacokinetics Test Using a Dog

Injectable preparations containing the dihydrate of the presentinvention as an active ingredient were formulated as shown in Table 3.Each of the injectable preparations was injected into the thigh muscleof a dog in such a dosage that 10 mg/kg of active ingredient calculatedas the anhydride of the present invention was contained. FIG. 14 is agraph showing the mean blood concentration-time profile after theinjection. As is clear from FIG. 14, the sustained release property canbe stably maintained for more than 30 days from the injection.Stimulation at the injection site was observed days after the injectionand the results showed that the stimulation was low.

TABLE 3 Test Example 2 Component Amount (mg) Dihydrate of the presentinvention 108 Sorbitol 50 Sodium carboxymethylcellulose 10 Sodiumdihydrogenphosphate dihydrate 0.78 Benzyl benzoate 1 Polysorbate 80 2Sodium hydroxide Q.S. (pH 7.0) Injection water Q.S. Total 1 mL

1. A dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or of a salt thereof.
 2. A method forpreventing and/or treating a central nervous system disease comprising adihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or of a saltthereof as an active ingredient.
 3. The method according to claim 2which is for preventing or treating a central nervous system diseaseselected from the group consisting of schizophrenia,treatment-resistant, refractory and chronic schizophrenia, emotionaldisturbance, psychotic disorder, mood disorder, bipolar disorder, mania,depression, endogenous depression, major depression, melancholic andtreatment-resistant depression, dysthymic disorder, cyclothymicdisorder, anxiety disorder, somatoform disorder, factitious disorder,dissociative disorder, sexual disorder, eating disorder, sleep disorder,adjustment disorder, substance-related disorder, anhedonia, delirium,cognitive impairment, cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease, and other neurodegenerative diseases, BPSDcaused by cognitive impairment, cognitive impairment in schizophrenia,cognitive impairment caused by treatment-resistant, refractory orchronic schizophrenia, vomiting, motion sickness, obesity, migraine,pain, mental retardation, autism, Tourette's syndrome, tic disorder,attention deficit hyperactivity disorder, conduct disorder, and Down'ssyndrome.